The invention relates to a pharmaceutical including a macrolide antibiotic. The invention also relates to a process for manufacturing the pharmaceutical.
The compounds Erythromycin, Roxithromycin, Clarithromycin, Azithromycin and Dirithromycin are widely used macrolide antibiotics for the treatment of various types of infections. The chemical structures of these macrolides as follows. 
It is known that the stability and the pharmacological and immunomicrobiological profile of these compounds can be improved by derivatisation and by conversion into various salts.
EP-A-0057489 describes salts of Erythromycin and Erythromycin propionate with N-acetylcysteine, carboxymethylcysteine, thiazolidin-carboxylic acid and mercapto-succinic acid. However these salts are sensitive to sunlight, humidity and heat.
WO-A-96/19489 describes a salt of Roxithromycin with N-acetylcysteine.
There is a need for a pharmaceutical including a macrolide antibiotic which will have an enhanced pharmaceutical profile.
According to the invention there is provided a pharmaceutical comprising:
a mucolytic and
an antibiotic, pharmaceutically acceptable salts or esters thereof,
wherein the mucolytic is present in an amount of greater than one molar equivalent of the antibiotic.
In a preferred embodiment of the invention the antibiotic is selected from:
Erythromycin;
Roxithromycin;
Clarithromycin;
Azithromycin;
Dirithromycin; and
pharmaceutically acceptable salts or esters thereof.
Preferably the mucolytic is a mucolytically active thiol. Usually the mucolytically active thiol is selected from:
N-acetylcysteine;
mercaptoethanesulfonic acid;
tiopronin; and
methylcysteine.
Preferably the mucolytic is present in an amount of less than about four molar equivalents of the antibiotic. Most preferably the mucolytic is present in an amount of less than two molar equivalents of the antibiotic.
In a preferred embodiment of the invention the pharmaceutical includes a compound of the formula
[RH⊕][Xxe2x8ax96]
wherein
R is a radical selected from:
Erythromycin;
Clarithromycin;
Roxithromycin;
Azithromycin;
Dirithromycin;
pharmaceutically acceptable esters thereof; and
HX is a mucolytically active thiol.
In one embodiment of the invention the pharmaceutical includes a compound of the formula
[RH⊕][Yxe2x8ax96]
wherein
R is as defined above and
HY is a pharmaceutically acceptable inorganic or organic acid.
In another embodiment of the invention the pharmaceutical includes a compound of the formula:
[RH⊕(HX*)n][Xxe2x8ax96]
wherein
R and HX are as defined above,
HX* is a bound mucolytically active thiol; and
n is a number greater than zero.
For example n may be 1, 2 or 3.
The invention also provides a pharmaceutical including a compound of the formula
[RH⊕(HX*)][Xxe2x8ax96]
and compounds of the formulae:
[RH⊕(HX*)2][Xxe2x8ax96]
[RH⊕(HX*)3][Xxe2x8ax96]
wherein R, HX and HX* are as defined above.
The pharmaceutical may include a compound of the formula:
[RH⊕(HX*)n][Yxe2x8ax96]
wherein
R and HX* are as defined above;
HY is a pharmaceutically acceptable inorganic or organic acid; and
n is a number greater than zero.
For example n may be 1, 2 or 3.
In a preferred embodiment of the invention the pharmaceutical includes a compound of the formula:
[RH⊕(HX*)][Yxe2x8ax96]
and compounds of the formulae:
[RH⊕(HX*)2][Yxe2x8ax96]
[RH⊕(HX*)3][Yxe2x8ax96]
wherein R, HX* and HY are as defined above.
The invention also provides a compound of the formula:
[RH⊕(HX*)n][Xxe2x8ax96]
wherein R, HX, HX* and n are as defined above.
The invention further provides a compound of the formula:
[RH⊕(HX*)][Xxe2x8ax96]
wherein R, HX and HX* are as defined above.
In addition, the invention provides compounds of the formulae:
[RH(HX*)2][X]
[RH(HX*)3][X]
wherein R, HX and HX* are as defined above.
The invention also provides a compound of the formula:
[RH⊕(HX*)n][Xxe2x8ax96]
wherein R, HX*, HY and n are as defined above.
The invention also provides a compound of the formula:
[RH⊕(HX*)][Yxe2x8ax96]
wherein R, HX* and HY are as defined above.
The invention further provides compounds of the formulae:
[RH⊕(HX*)2][Yxe2x8ax96]
[RH⊕(HX*)3][Yxe2x8ax96]
wherein R, HX* and HY are as defined above.
The invention also provides a process for preparing a compound of the formula:
[RX⊕(HX*)n][Xxe2x8ax96]
wherein R, HX, HX* and n are as defined above by reacting a compound of the formula R with a desired molar equivalent(s) of a compound of the formula HX.
The process may include the step of forming, as an intermediate, a compound of the formula:
[RH][X]
wherein R and HX are as defined above.
According to another aspect the invention provides a process for preparing a compound of the formula:
[RH⊕(HX*)n][Yxe2x8ax96]
wherein R, HX*, HY and n are as defined above by reacting a compound of the formula R with a compound of the formula HY to form a compound of the formula:
[RH][Y]
which is reacted with a desired molar equivalent(s) of a compound of the formula HX wherein R, HX and HY are as defined above.
Preferably the process is carried out in the presence of water.
Ideally the process is carried out at a temperature of from 15 to 45xc2x0 C., preferably at a temperature of from 20 to 25xc2x0 C.
In another aspect the invention provides a pharmaceutical composition in solid form incorporating a compound of the invention.
It has surprisingly been found that the pharmacological profile of [1:1] antibiotic-mucolytic agents can be improved. In particular the mucolytic effect can be increased by preparing salts of macrolide antibiotics with an additional amount of mucolytic agent.
It has also surprisingly been found that novel adducts with a molar ratio higher than [1:1] (antibiotic-mucolytic agent) can be isolated via a very simple and efficient process. Such adducts can for example be integer [1:2]-, [1:3]- or [1:4] compounds bearing a one, two or three molar excess of mucolytic relative to the equivalent of antibiotic. Alternatively any type of non-integer adducts in the range between [1:1] and [1:4] may also be prepared.
Especially Erythromycin A or its pharmaceutically acceptable esters, Roxithromycin, Clarithromycin or Azithromycin are suitable to form such an adduct with mucolytically active thiols, in particular with N-acetylcysteine. The reaction is ideally performed under aqueous conditions affording the products in high yield and very good quality.
The invention provides novel macrolide antibiotics bearing a mucolytically active component as shown in scheme 2:
R is a radical preferably selected from Erythromycin A or its pharmaceutically acceptable esters, Clarithromycin, Roxithromycin or Azithromycin.
HX is a mucolytically active thiol, preferably selected from N-acetylcysteine, mercaptoethanesulfonic acid, tiopronin or methylcysteine.
HX* is a bound mucolytically active thiol, preferably N-acetylcysteine, mercaptoethanesulfonic acid, tiopronin or methylcysteine.
R can be converted into its acid-base addition salt (I) by reaction with a mucolytically active thiol HX.
Adduct (II) can be obtained by reacting (I) with a second equivalent of HX; alternatively R can directly be converted into (II) using two equivalents of HX. The formation of compounds (III) and (IV) may be achieved by direct reaction of R with 3 or 4 equivalents of HX. Alternatively stepwise conversion may be performed by reacting R portion wise with HX as outlined in scheme 2.
If non-integer equivalents of HX greater than one are used, mixtures of the compounds (I), (II), (III) and (IV) may be isolated depending on the added amount of HX.
Optionally the antibiotic R can initially be reacted with an inorganic or organic acid HY into a pharmaceutically acceptable acid-base addition salt of type:
[RH][Y]
This salt may then be further converted by reaction with HX into compounds of the following formulae and mixtures thereof:
[RH⊕(HX)*][Yxe2x8ax96]
[RH⊕(HX)*2][Yxe2x8ax96]
[RH⊕(HX)*3][Yxe2x8ax96]
The reaction takes place in an analogous way to the process shown in scheme 2.
The process is preferably performed in the presence of water.
The most preferred mucolytic is N-acetylcysteine.
The invention will be more clearly understood by means of the following examples:
The macrolide antibiotic and the mucolytic are homogenised for 1-2 h preferably at room temperature. Process water is then added and homogenisation is continued for 1-2 h at a temperature of 15-45xc2x0 C., preferably at 20-25xc2x0 C. The product is dried under vacuum and isolated in quantitative yield. Optionally the product may be milled. The process may, for example, be carried out using an INOX dryer as described in WO-A-9619489.